The present application is a reissue of Ser. No. 08/216,590, filed Mar. 23, 1994.
1. Field of the Invention
The present invention relates to the management of an individual""s pain by administering liposome encapsulated opioids to the individual through the pulmonary system.
2. Description of the Related Art
Liposomes are microscopic vesicles composed of an aqueous compartment surrounded by a phospholipid bilayer which acts as a permeable entrapment barrier, for example for drug molecules (Gangham A. D., et al: J Mol Biol: 13:238-252, 1965). There are many types of liposomes that can be used in various routes of drug administration (see a recent review by Gregoriadis (ed.) in Liposome Technology, 2nd edition, vol I-III, CRC Press, Boca Ranto, Fla., 1993). Certain types of liposomes can provide a controlled, sustained release system (Mezei M: In Controlled release dosage forms. Tipnis HP (ed): Bombay College of Pharmacy, India, 1988, pp 37-46). In such a system, the rate of drug release is primarily determined by the liposome""s physicochemical properties. Liposomes can be tailored for a specific application by modification of size, composition, and surface charge to provide the desired rate of drug delivery (Meisner D, et al: In Proceedings, 15th International Symposium on Controlled Release of Bioactive Materials. 15:262-263, 1988; Mezei M: In Drug Permeation Enhancement, Theory and Application Hsich DS (ed): Marcel Dekker Inc., New York, 1993, pp 171-198; and Meisner D, et al: J Microencapsulation 6:379-387, 1989). Decades of research in liposome technology has indicated that liposome-encapsulation is an effective and safe drug delivery system.
Liposomes have been used clinically as intravenous drug carrier systems in enzyme replacement therapy (Belchetz P. E., et al: Lancet ii:116-117, 1977), in anti-fungal therapy (Lopez-Gerenstein G, et al: J Infect Dis 151:704-709, 1985), and in chemotherapy (Sculier J. P., et al: J Clin Oncol 4:789-797, 1986). Liposome encapsulation of local anesthetics provides intensified and prolonged action, when applied on the skin (Gesztes and Mezei: Anesth Anag 67: 1079-1081, 1988; Mezei and Gesztes: U.S. Pat. No. 4,973,078, 1990). Liposome-encapsulated alfentanil administered intrathecally produced prolonged spinal anesthesia in rats (Bernards, et al: Anesthesiology, 77:529-535, 1992).
Despite years of therapeutic advances, acute and chronic pain remain major medical problems. Acute pain following surgical procedures has been associated with adverse physiological alterations in the pulmonary (Ford G. T., et al: Am Rev Resp Dis 127:431, 1983), cardiovascular (Ready B: In Anesthesia, 3rd edition, Miller RD (ed), Churchill Livingstone, New York, 1990 pp. 2135-2146), gastrointestinal, urinary (Cousins M: In Textbook of Pain, 2nd Edition, Wall, Melzack (eds): Churchill Livingstone, New York, 1989, pp 284-305.) and neuroendocrine systems (Kehlet H: In Acute Pain Management. Cousin and Phillips (eds): Churchill Livingstone, New York, 1986, pp 49). Many of these undesirable physiological changes can be minimized with effective analgesia (Cousins M: In Textbook of Pain, 2nd Edition. Wall, Melzack (eds): Churchill Livingstone, New York, 1989, pp 284-305). While systemic administration of opiods remains the most common treatment method of acute pain management, their on-demand intermittent intramuscular administration has been shown to be ineffective in managing pain in hospitalized patients (Ready B: In Anesthesia, 3rd edition, Miller RD (ed), Churchill Livingstone, New York, 1990 pp 2135-2146; Cousins M: In Textbook of Pain, 2nd Edition, Wall and Melzack (eds): Churchill Livingstone, New York, 1989, pp 284-305; and Austin K. L., et al: Pain 8:47, 1980). Recent advances in pain management using spinal or epidural administration of opiods provide effective alternatives for acute pain management. However, these analgesic methods are invasive, and are associated with significant complications and costs. Three advances in clinical pharmacology have attempted to address these shortcomings: oral sustained-release opiods, patient-controlled analgesia, and transdermal drug delivery. These three approaches have respective advantages in terms of safety, efficacy, and cost.
Oral sustained-release opiods (e.g. MS CONTIN (trademark)) have provided an effective, and fairly inexpensive, means of administering opiods to patients with chronic pain (Khojasthe A., et al: J Clin Oncology 5:956-61, 1987). Unfortunately, the use of an oral route makes this method unavailable to many hospitalized patients with acute pain who may have gastrointestinal dysfunction from cancer or following surgery (Banning A. M., et al: Anesth Anag 65:385-8, 1986). Additionally, plasma levels obtained from oral preparations show wide variability because of individual variations in tablet dissolution, intragastric pH, intragastric motility, and hepatic first pass metabolism (Khojasthe A., et al: J Clin Oncology 5:956-61, 1987).
Patient-controlled analgesia (PCA) using an infusion pump, has been shown to be effective in providing post-operative analgesia (White P. F.: JAMA 259-243, 1988). The major advantage of this technique is that titration by the patient compensates for pharmacokinetic and pharmacodynamic variability, and thus potentially produces adequate analgesia. Because PCA requires continuous intravenous access and maintenance of both the pump and infusion line, however, this method of analgesia is usually limited to hospitalized patients (Albert J. M., et al: Dis Colon Rectum 31:83-6, 1988). Even so, the major limitation of PCA is cost. The pump, prefilled syringes and specialized tubing that are used with PCA are expensive, as are the personnel required to maintain intravenous access (White P. F.: Anesthesiology 66:81-3, 1987).
Transdermal fentanyl delivery was recently introduced to overcome the shortcomings of oral sustained-release analgesics and PCA. The advantages of such a system are that it is entirely non-invasive and, can maintain a plateau of analgesia for up to three days following application. However, variability in physical properties of the stratum-corneum of the dermis creates more than 50% variability in fentanyl absorption (Varvel J. R., et al: Anesthesiology 70:928-934, 1989). Even though the device was developed using an acute pain model (Caplan R. A., et al: JAMA 261:1036-1039, 1992), the variability is so high that transdermal fentanyl has only been approved for use in cases of chronic pain. Additionally, transdermal fentanyl may not be appropriate for acute post-operative pain management since the drug concentration initially rises very slowly, reaching a plateau 12-16 hours following application of the fentanyl patch. Lastly, the fentanyl patches are expensive. Thus, high variability, slow onset, and moderately high cost all limit the application of transdermal fentanyl (Varvel J. R., et al: Anesthesiology 70:928-934, 1989).
Administration of an opioid, such as fentanyl, through the pulmonary system using a nebulizer has recently been reported for providing postoperative analgenia (Worsley M. H., et al: Anaesthesia 1990, 45:449-451; and Higgins M. J., et al: Anaesthesia 1991, 46:973-976). The duration of analgesia was short due to rapid clearance of fentanyl from the lungs.
Certain liposome-encapsulated drugs administered via the pulmonary route have provided sustained release and, therefore, prolonged drug action (Mihalko P. J., et al: In Liposomes as Drug Carriers, Gregoriadis (ed.), John Wiley and Sons Ltd. Toronto, 1988, pp 679-694; Meisner D., et al: J Microencapsulation 6:379-387, 1989 and Meisner D.: In Pharmaceutical Particulate Carriers: Therapeutic Application. Roland A (ed), Marcel Dekker Inc. New York 1993, pp 31-63). Liposomal drug delivery to the lungs appears to be well tolerated in both animals and humans. In animal models with rabbits and mice, acute and chronic inhalation of liposome aerosol did not adversely affect lung appearance, cell consistency, or pulmonary histopathology (Oyarzum M. J., et al: An Rev Resp Dis 121:709-721, 1980, and Myers M. A., et al: An Rev Resp Dis 141:A675, 1990). No adverse effects have been associated with inhalation of exogenous phospholipids to preterm infants with respiratory distress syndrome (Ivey H., et al: Pediatr Res 11:573, 1977 and Morely C. J., et al: Lancet i:64-68, 1981). Thomas and colleagues (Thomas, et al: Chest 99: 1268-1270, 1991) reported no oxygen desaturation, deterioration in pulmonary function or side effects associated with the inhalation of liposomes in healthy human volunteers.